Malaria parasites, which cause approximately one million deaths annually, undergo sexual differentiation and development in the Anopheline mosquitoes. The sexual life cycle and transmission of Plasmodium parasites can be blocked when a refractory mosquito mounts an innate immune response against the parasites it carries. The objective of this proposal is to understand the genetic basis of refractory mechanisms in the mosquito. Anopheles gambiae is a principal vector for human malaria in Africa. A major type of immune response by this vector against Plasmodium parasites is the encapsulation of oocysts within melanin capsules in the mosquito midgut. The current knowledge of the genetic basis of this refractory response is very limited, except that three dominant quantitative trait loci (QTLs) have been identified against Plasmodium cynomolgi B. This proposal will take a combined approach of genetic mapping and QTL analyses to address four questions of broad interests. (1) How many QTLs in An. gambiae are required for the encapsulation response? (2) How do these QTLs interact and what is the sequence of events during the response? (3) Are all the QTLs effective against all Plasmodium, or is there a bias for a particular QTL against certain parasites species? (4) Are all the QTLs required for the encapsulation of Plasmodium falciparum, the most virulent human parasite. These questions will be answered through the genetic and QTL analyses of the encapsulation responses by different strains and colonies of mosquitoes against a variety of Plasmodium parasites. The parasites used will include rodent parasite Plasmodium berghei, simian parasite Plasmodium cynomolgi, and human parasite P. falciparum. This study constitutes a first comprehensive effort to understand the genetic basis of the encapsulation response. Achievements will advance the basic knowledge to the innate immunity of insects and higher eucaryotes. The knowledge gained will also contribute to the future innovative strategies for the control of malaria transmission.